The increased prevalence of multidrug resistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacterial viruses or bacteriophages (phages). Throughout this century the therapeutic application of phages as antibacterial agents was impeded by several factors: first, the failure to recognize the relatively narrow host range of phages; second, the presence of toxins in unpurified phage preparations; and third, a lack of appreciation for the capacity of mammalian host defense systems, particularly the organs of the reticuloendothelial system (RES), to remove phage particles from the circulatory system. In our studies involving bacteremic mice, the problem of the narrow host range of phage was dealt with by using selected bacterial strains and virulent phage specific for them. Toxin levels were diminished by purifying phage preparations. To reduce phage elimination by the host defense system, we developed a serial passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time. By this approach we isolated long-circulating mutants of phage for two different species of bacteria. We demonstrated that these long-circulating phage mutants also have greater capability as antibacterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. The use of toxin-free, bacteria-specific phage strains, combined with the serial passage technique, may provide insights for developing phage into therapeutically effective antibacterial agents which could significantly augment our ability to treat infectious diseases. There are a number of infectious diseases that affect the CNS directly and indirectly that may benefit from the development of such therapeutic agents. In addition, the approach taken in this effort provides a paradigm for the development of gene therapy vectors that also may be of use in the future in the treatment of diseases of the CNS that result from inborn errors of metabolism.